BERKELEY, CA (UroToday.com) - Current clinical practice has been driven largely by the widespread use of PSA. Serum PSA levels showed limited specificity, particularly in PSA range 2-10 ng/ml.
Several studies have indicated that reflex tests based on PSA isoforms can improve cancer detection in men with tPSA levels between 2 and 10 ng/ml. In particular, it has been widely accepted that a low %fPSA is a useful test to reduce the number of unnecessary biopsies. fPSA fraction is composed of at least three different types of enzymatically inactive PSA: benign PSA (BPSA), intact inactive PSA, and proPSA, of which BPSA and proPSA are the best characterized. In PCa patients, serum proPSA is comprised primarily of a truncated form of proPSA that contains a pro-leader peptide consisting of only two ([-2]proPSA) rather than the usual seven amino acids ([-7]proPSA). Thus, serum proPSAs gained attention as a potentially specific form of fPSA that may help overcome the current limitations of %fPSA, reducing the highest number of unnecessary biopsies. On the basis of substantial evidence for the role of [-2]proPSA in early prostate cancer detection, Beckman Coulter Inc. developed a mathematical algorithm incorporating [-2]proPSA, tPSA and fPSA for use in patients with PSA levels of 2–10 ng/mL with a non-suspicious prostate on DRE.

This meta-analysis is the first study that compares the published data on the clinical usefulness of PHI compared to %fPSA in subjects undergoing first prostate biopsy with PSA levels in the 2-10 ng/ml. The results of this meta-analysis showed that use of PHI index compared to %fPSA could improve the detection of prostate cancer in men who have PSA levels of 2-10 ng/ml. Of note, an increasing number of patients are being diagnosed with potentially low-risk, clinically insignificant cancers. In these patients, active surveillance has been proposed as an alternative treatment strategy with the aim of reducing the risk of radical prostatectomy side effects. However, we currently lack an ideal definition of indolent PCa, and circulating biomarkers could be a promising tool to identify patients harboring aggressive disease. Unfortunately, at present only few studies evaluated the usefulness of PHI as predictor of aggressive PCa, impeding the ability to perform meta-analysis. Further studies are required to better address this issue.

Within a specific prostate cancer detection plan, a cost-benefit analysis needs to be carried out to quantify whether the extra costs of a PHI test, with its corresponding reduced numbers of biopsies, will offer a net saving to the health care provider. Taking in account that the cost of %fPSA is clearly higher than PSA alone, and PHI index can be expected to reduce false negative tests, the use of PHI instead of %fPSA as reflex test in tPSA range 2-10 ng/ml may decrease the global costs and disutility related to the prostate biopsy procedure.

In conclusion, our results suggested that PHI index in patients with “gray” values of tPSA may be a better predictor of positive biopsy compared to %fPSA. Therefore, the use of PHI index can offer a reduction in unnecessary biopsies whilst maintaining a high cancer detection rate. However, given PCa heterogeneity, moving forward, efforts to increase diagnostic accuracy must focus on a combination of biomarkers. Promising results have been obtained by the combination of PCA3 with TMPRSS2:ERG and with PHI.

In the future, more studies are needed to define the optimal PHI cut-off value and to evaluate the ability of PHI in the discrimination of indolent and aggressive PCa. Finally, worthy of further attention is the potential improvement in diagnostic performance of the combination of PHI with other biomarkers.

Written by:Dario Bruzzese,a Claudia Mazzarella,b Matteo Ferro,c Sisto Perdonà,d Paolo Chiodini,e Giuseppe Perruolo,b and Daniela Terracciano,b as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

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